Cancer Letters
Volume 234, Issue 2 , Pages 109-123 , 28 March 2006

Gonadotropin-releasing hormone in apoptosis of prostate cancer cells

  • Sarah Kraus

      Affiliations

    • Department of Microbiology and Cancer Center, University of Virginia, Charlottesville, VA 22908, USA
  • ,
  • Zvi Naor

      Affiliations

    • Department of Biochemistry, Tel Aviv University, Ramat Aviv 69978, Israel
  • ,
  • Rony Seger

      Affiliations

    • Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel
    • Corresponding Author InformationCorresponding author. Tel. :+972 8 9343602; fax: +972 8 9344116.

Received 24 February 2005 ,Accepted 28 February 2005.

References 

  1. Neill JD, Musgrove LC, Duck LW. Newly recognized GnRH receptors: function and relative role. Trends Endocrinol. Metab. 2004;15:383–392
  2. Ruf F, Sealfon SC. Genomics view of gonadotrope signaling circuits. Trends Endocrinol. Metab. 2004;15:331–338
  3. Millar RP, Lu ZL, Pawson AJ, Flanagan CA, Morgan K, Maudsley SR. Gonadotropin-releasing hormone receptors. Endocr. Rev. 2004;25:235–275
  4. Cheng CK, Leung PC. Molecular biology of gonadotropin-releasing hormone (GnRH)-I, GnRH-II and their receptors in humans. Endocr. Rev. 2004;
  5. Fink G. Gonadotropin secretion and its control. In:  Knobil E,  Neill JD editor. The Physiology of Reproduction. New York, NY: Raven Press; 1988;p. 1349–1377
  6. Conn PM, Crowley WF. Gonadotropin-releasing hormone and its analogs. Annu. Rev. Med. 1994;45:391–405
  7. Casper RF. Clinical uses of gonadotropin-releasing hormone analogues. Can. Med. Assoc. J. 1991;144:153–158
  8. Emons G, Schally AV. The use of luteinizing hormone releasing hormone agonists and antagonists in gynaecological cancers. Hum. Reprod. 1994;9:1364–1379
  9. Filicori M. Gonadotrophin-releasing hormone agonists. A guide to use and selection. Drugs. 1994;48:41–58
  10. Miyamoto H, Messing EM, Chang C. Androgen deprivation therapy for prostate cancer: current status and future prospects. Prostate. 2004;61:332–353
  11. Segal-Abramson T, Kitroser H, Levy J, Schally AV, Sharoni Y. Direct effects of luteinizing hormone-releasing hormone agonists and antagonists on MCF-7 mammary cancer cells. Proc. Natl Acad. Sci. USA. 1992;89:2336–2339
  12. Kottler ML, Starzec A, Carre MC, Lagarde JP, Martin A, Counis R. The genes for gonadotropin-releasing hormone and its receptor are expressed in human breast with fibrocystic disease and cancer. Int. J. Cancer. 1997;71:595–599
  13. Emons G, Ortmann O, Becker M, Irmer G, Springer B, Laun R, et al. High affinity binding and direct antiproliferative effects of LHRH analogues in human ovarian cancer cell lines. Cancer Res. 1993;53:5439–5446
  14. Srkalovic G, Wittliff JL, Schally AV. Detection and partial characterization of receptors for [D-Trp6]-luteinizing hormone-releasing hormone and epidermal growth factor in human endometrial carcinoma. Cancer Res. 1990;50:1841–1846
  15. Chatzaki E, Bax CM, Eidne KA, Anderson L, Grudzinskas JG, Gallagher CJ. The expression of gonadotropin-releasing hormone and its receptor in endometrial cancer, and its relevance as an autocrine growth factor. Cancer Res. 1996;56:2059–2065
  16. Bahk JY, Hyun JS, Lee H, Kim MO, Cho GJ, Lee BH, et al. Expression of gonadotropin-releasing hormone (GnRH) and GnRH receptor mRNA in prostate cancer cells and effect of GnRH on the proliferation of prostate cancer cells. Urol Res. 1998;26:259–264
  17. Limonta P, Moretti RM, Marelli MM, Dondi D, Parenti M, Motta M. The luteinizing hormone-releasing hormone receptor in human prostate cancer cells: messenger ribonucleic acid expression, molecular size, and signal transduction pathway. Endocrinology. 1999;140:5250–5256
  18. Tieva A, Stattin P, Wikstrom P, Bergh A, Damber JE. Gonadotropin-releasing hormone receptor expression in the human prostate. Prostate. 2001;47:276–284
  19. Grundker C, Volker P, Schulz KD, Emons G. Luteinizing hormone-releasing hormone agonist triptorelin and antagonist cetrorelix inhibit EGF-induced c-fos expression in human gynecological cancers. Gynecol. Oncol. 2000;78:194–202
  20. Marelli MM, Moretti RM, Dondi D, Motta M, Limonta P. Luteinizing hormone-releasing hormone agonists interfere with the mitogenic activity of the insulin-like growth factor system in androgen-independent prostate cancer cells. Endocrinology. 1999;140:329–334
  21. Emons G, Weiss S, Ortmann O, Grundker C, Schulz KD. LHRH might act as a negative autocrine regulator of proliferation of human ovarian cancer. Eur. J. Endocrinol. 2000;142:665–670
  22. Limonta P, Montagnani Marelli RM, Moretti RM. LHRH analogues as anticancer agents: pituitary and extrapituitary sites of action. Expert Opin. Investig. Drugs. 2001;10:709–720
  23. Kraus S, Levy G, Hanoch T, Naor Z, Seger RM. Gonadotropin-releasing hormone induces apoptosis of prostate cancer cells: role of c-Jun NH2-terminal kinase, protein kinase B, and extracellular signal-regulated kinase pathways. Cancer Res. 2004;64:5736–5744
  24. Maudsley S, Davidson L, Pawson AJ, Chan R, de Maturana RL, Millar RP. Gonadotropin-releasing hormone (GnRH) antagonists promote proapoptotic signaling in peripheral reproductive tumor cells by activating a Galphai-coupling state of the type I GnRH receptor. Cancer Res. 2004;64:7533–7544
  25. Miles LE, Hanyaloglu AC, Dromey JR, Pfleger KD, Eidne KA. Gonadotropin-releasing hormone receptor-mediated growth suppression of immortalized LbetaT2 gonadotrope and stable HEK293 cell lines. Endocrinology. 2004;145:194–204
  26. Schally AV, Arimura A, Kastin AJ, Matsuo H, Baba Y, Redding TW, et al. Gonadotropin-releasing hormone: one polypeptide regulates secretion of luteinizing and follicle-stimulating hormones. Science. 1971;173:1036–1038
  27. Dubois EA, Zandbergen MA, Peute J, Goos HJ. Evolutionary development of three gonadotropin-releasing hormone (GnRH) systems in vertebrates. Brain Res. Bull. 2002;57:413–418
  28. Sealfon SC, Weinstein H, Millar RP. Molecular mechanisms of ligand interaction with the gonadotropin-releasing hormone receptor. Endocr. Rev. 1997;18:180–205
  29. Troskie B, Illing N, Rumbak E, Sun YM, Hapgood J, Sealfon S, et al. Identification of three putative GnRH receptor subtypes in vertebrates. Gen. Comp. Endocrinol. 1998;112:296–302
  30. Reinhart J, Mertz LM, Catt KJ. Molecular cloning and expression of cDNA encoding the murine gonadotropin-releasing hormone receptor. J. Biol. Chem. 1992;267:21281–21284
  31. Tsutsumi M, Zhou W, Millar RP, Mellon PL, Roberts JL, Flanagan CA, et al. Cloning and functional expression of a mouse gonadotropin-releasing hormone receptor. Mol. Endocrinol. 1992;6:1163–1169
  32. Neill JD, Duck LW, Sellers JC, Musgrove LC. A gonadotropin-releasing hormone (GnRH) receptor specific for GnRH II in primates. Biochem. Biophys. Res. Commun. 2001;282:1012–1018
  33. Faurholm B, Millar RP, Katz AA. The genes encoding the type II gonadotropin-releasing hormone receptor and the ribonucleoprotein RBM8A in humans overlap in two genomic loci. Genomics. 2001;78:15–18
  34. Millar RP. GnRH II and type II GnRH receptors. Trends Endocrinol. Metab. 2003;14:35–43
  35. Wang L, Bogerd J, Choi HS, Seong JY, Soh JM, Chun SY, et al. Three distinct types of GnRH receptor characterized in the bullfrog. Proc. Natl Acad. Sci. USA. 2001;98:361–366
  36. Naor Z. Signal transduction mechanisms of Ca2+mobilizing hormones: the case of gonadotropin-releasing hormone. Endocr. Rev. 1990;11:326–353
  37. Stojilkovic SS, Tomic M, Kukuljan M, Catt KJ. Control of calcium spiking frequency in pituitary gonadotrophs by a single-pool cytoplasmic oscillator. Mol. Pharmacol. 1994;45:1013–1021
  38. Poulin B, Rich N, Mas JL, Kordon C, Enjalbert A, Drouva SV. GnRH signalling pathways and GnRH-induced homologous desensitization in a gonadotrope cell line (alphaT3-1). Mol. Cell. Endocrinol. 1998;142:99–117
  39. Shacham S, Harris D, Ben-Shlomo H, Cohen I, Bonfil D, Przedecki F, et al. Mechanism of GnRH receptor signaling on gonadotropin release and gene expression in pituitary gonadotrophs. Vitam. Horm. 2001;63:63–90
  40. Naor Z, Benard O, Seger R. Activation of MAPK cascades by G-protein-coupled receptors: the case of gonadotropin-releasing hormone receptor. Trends Endocrinol. Metab. 2000;11:91–99
  41. McArdle CA, Franklin J, Green L, Hislop JN. Signalling, cycling and desensitisation of gonadotrophin-releasing hormone receptors. J. Endocrinol. 2002;173:1–11
  42. Kraus S, Naor Z, Seger R. Intracellular signaling pathways mediated by the gonadotropin-releasing hormone (GnRH) receptor. Arch. Med. Res. 2001;32:499–509
  43. Harris D, Chuderland D, Bonfil D, Kraus S, Seger R, Naor Z. Extracellular signal-regulated kinase and c-Src, but not Jun N-terminal kinase, are involved in basal and gonadotropin-releasing hormone-stimulated activity of the glycoprotein hormone alpha-subunit promoter. Endocrinology. 2003;144:612–622
  44. Roberson MS, Misra-Press A, Laurance ME, Stork PJ, Maurer RA. A role for mitogen-activated protein kinase in mediating activation of the glycoprotein hormone alpha-subunit promoter by gonadotropin-releasing hormone. Mol. Cell. Biol. 1995;15:3531–3539
  45. Harris D, Bonfil D, Chuderland D, Kraus S, Seger R, Naor Z. Activation of MAPK cascades by GnRH: ERK and Jun N-terminal kinase are involved in basal and GnRH-stimulated activity of the glycoprotein hormone LHbeta-subunit promoter. Endocrinology. 2002;143:1018–1025
  46. Bonfil D, Chuderland D, Kraus S, Shahbazian D, Friedberg I, Seger R, et al. Extracellular signal-regulated kinase, Jun N-terminal kinase, p38, and c-Src are involved in gonadotropin-releasing hormone-stimulated activity of the glycoprotein hormone follicle-stimulating hormone beta-subunit promoter. Endocrinology. 2004;145:2228–2244
  47. Lin X, Conn PM. Transcriptional activation of gonadotropin-releasing hormone (GnRH) receptor gene by GnRH: involvement of multiple signal transduction pathways. Endocrinology. 1999;140:358–364
  48. Grundker C, Emons G. Role of gonadotropin-releasing hormone (GnRH) in ovarian cancer. Reprod. Biol. Endocrinol. 2003;1:65
  49. Shah BH, Catt KJ. Matrix metalloproteinases in reproductive endocrinology. Trends Endocrinol. Metab. 2004;15:47–49
  50. Benard O, Naor Z, Seger R. Role of dynamin, Src, and Ras in the protein kinase C-mediated activation of ERK by gonadotropin-releasing hormone. J. Biol. Chem. 2001;276:4554–4563
  51. Levi NL, Hanoch T, Benard O, Rozenblat M, Harris D, Reiss N, et al. Stimulation of Jun N-terminal kinase (JNK) by gonadotropin-releasing hormone in pituitary alpha T3-1 cell line is mediated by protein kinase C, c-Src, and CDC42. Mol. Endocrinol. 1998;12:815–824
  52. Roberson MS, Zhang T, Li HL, Mulvaney JM. Activation of the p38 mitogen-activated protein kinase pathway by gonadotropin-releasing hormone. Endocrinology. 1999;140:1310–1318
  53. Pierce KL, Luttrell LM, Lefkowitz RJ. New mechanisms in heptahelical receptor signaling to mitogen activated protein kinase cascades. Oncogene. 2001;20:1532–1539
  54. Kraus S, Benard O, Naor Z, Seger R. c-Src is activated by the epidermal growth factor receptor in a pathway that mediates JNK and ERK activation by gonadotropin-releasing hormone in COS7 cells. J. Biol. Chem. 2003;278:32618–32630
  55. Shah BH, Farshori MP, Catt KJ. Neuropeptide-induced transactivation of a neuronal epidermal growth factor receptor is mediated by metalloprotease-dependent formation of heparin-binding epidermal growth factor. J. Biol. Chem. 2004;279:414–420
  56. Stanislaus D, Ponder S, Ji TH, Conn PM. Gonadotropin-releasing hormone receptor couples to multiple G proteins in rat gonadotrophs and in GGH3 cells: evidence from palmitoylation and overexpression of G proteins. Biol. Reprod. 1998;59:579–586
  57. Hawes BE, Barnes S, Conn PM. Cholera toxin and pertussis toxin provoke differential effects on luteinizing hormone release, inositol phosphate production, and gonadotropin-releasing hormone (GnRH) receptor binding in the gonadotrope: evidence for multiple guanyl nucleotide binding proteins in GnRH action. Endocrinology. 1993;132:2124–2130
  58. Grundker C, Volker P, Emons G. Antiproliferative signaling of luteinizing hormone-releasing hormone in human endometrial and ovarian cancer cells through G protein alpha(I)-mediated activation of phosphotyrosine phosphatase. Endocrinology. 2001;142:2369–2380
  59. Imai A, Takagi H, Horibe S, Fuseya T, Tamaya T. Coupling of gonadotropin-releasing hormone receptor to Gi protein in human reproductive tract tumors. J. Clin. Endocrinol. Metab. 1996;81:3249–3253
  60. Imai A, Horibe S, Takagi A, Tamaya T. Gi protein activation of gonadotropin-releasing hormone-mediated protein dephosphorylation in human endometrial carcinoma. Am. J. Obstet. Gynecol. 1997;176:371–376
  61. Everest HM, Hislop JN, Harding T, Uney JB, Flynn A, Millar RP, et al. Signaling and antiproliferative effects mediated by GnRH receptors after expression in breast cancer cells using recombinant adenovirus. Endocrinology. 2001;142:4663–4672
  62. Lania A, Mantovani G, Ferrante E, Zavanone LM, Locatelli M, Corbetta S, et al. Gonadotropin-releasing hormone initiates multiple signaling pathways in human GH-secreting adenomas. J. Endocrinol. Invest. 2004;27:328–333
  63. Krsmanovic LZ, Mores N, Navarro CE, Arora KK, Catt KJ. An agonist-induced switch in G protein coupling of the gonadotropin-releasing hormone receptor regulates pulsatile neuropeptide secretion. Proc. Natl Acad. Sci. USA. 2003;100:2969–2974
  64. Liu F, Usui I, Evans LG, Austin DA, Mellon PL, Olefsky JM, et al. Involvement of both G(q/11) and G(s) proteins in gonadotropin-releasing hormone receptor-mediated signaling in L beta T2 cells. J. Biol. Chem. 2002;277:32099–32108
  65. Biebermann H, Schoneberg T, Schulz A, Krause G, Gruters A, Schultz G, et al. A conserved tyrosine residue (Y601) in transmembrane domain 5 of the human thyrotropin receptor serves as a molecular switch to determine G-protein coupling. Fed. Am. Soc. Exp. Biol. J. 1998;12:1461–1471
  66. Schwindinger WF, Fredericks J, Watkins L, Robinson H, Bathon JM, Pines M, et al. Coupling of the PTH/PTHrP receptor to multiple G-proteins. Direct demonstration of receptor activation of Gs, Gq/11, and Gi(1) by [alpha-32P]GTP-gamma-azidoanilide photoaffinity labeling. Endocrine. 1998;8:201–209
  67. Grosse R, Roelle S, Herrlich A, Hohn J, Gudermann T. Epidermal growth factor receptor tyrosine kinase mediates Ras activation by gonadotropin-releasing hormone. J. Biol. Chem. 2000;275:12251–12260
  68. Greenlee RT, Murray T, Bolden S, Wingo PA. Cancer statistics, 2000, CA. Cancer J. Clin. 2000;50:7–33
  69. Denmeade SR, Isaacs JT. Development of prostate cancer treatment: the good news. Prostate. 2004;58:211–224
  70. Labrie F, Cusan L, Gomez J, Luu-The V, Candas B, Belanger A, et al. Major impact of hormonal therapy in localized prostate cancer-death can already be an exception. J. Steroid Biochem. Mol. Biol. 2004;92:327–344
  71. Goethuys H, Baert L, Van Poppel H, Lieskovsky G, Brady LW, Petrovich Z. Treatment of metastatic carcinoma of the prostate. Am. J. Clin. Oncol. 1997;20:40–45
  72. Lau HL, Zhu XM, Leung PC, Chan LW, Chen GF, Chan PS, et al. Detection of mRNA expression of gonadotropin-releasing hormone and its receptor in normal and neoplastic rat prostates. Int. J. Oncol. 2001;19:1193–1201
  73. Kakar SS, Grantham K, Musgrove LC, Devor D, Sellers JC, Neill JD. Rat gonadotropin-releasing hormone (GnRH) receptor: tissue expression and hormonal regulation of its mRNA. Mol. Cell. Endocrinol. 1994;101:151–157
  74. Ravenna L, Salvatori L, Morrone S, Lubrano C, Cardillo MR, Sciarra F, et al. Effects of triptorelin, a gonadotropin-releasing hormone agonist, on the human prostatic cell lines PC3 and LNCaP. J. Androl. 2000;21:549–557
  75. Limonta P, Dondi D, Moretti RM, Maggi R, Motta M. Antiproliferative effects of luteinizing hormone-releasing hormone agonists on the human prostatic cancer cell line LNCaP. J. Clin. Endocrinol. Metab. 1992;75:207–212
  76. Pinski J, Reile H, Halmos G, Groot K, Schally AV. Inhibitory effects of analogs of luteinizing hormone-releasing hormone on the growth of the androgen-independent Dunning R-3327-AT-1 rat prostate cancer. Int. J. Cancer. 1994;59:51–55
  77. Szende B, Srkalovic G, Groot K, Lapis K, Schally AV. Regression of nitrosamine-induced pancreatic cancers in hamsters treated with luteinizing hormone-releasing hormone antagonists or agonists. Cancer Res. 1990;50:3716–3721
  78. Dondi D, Moretti RM, Marelli MM, Motta M, Limonta P. Growth factors in steroid-responsive prostatic tumor cells. Steroids. 1996;61:222–225
  79. Motta M, Dondi D, Moretti RM, Montagnani Marelli M, Pimpinelli F, Maggi R, et al. Role of growth factors, steroid and peptide hormones in the regulation of human prostatic tumor growth. J. Steroid Biochem. Mol. Biol. 1996;56:107–111
  80. Dondi D, Moretti RM, Montagnani Marelli M, Pratesi G, Polizzi D, Milani M, et al. Growth-inhibitory effects of luteinizing hormone-releasing hormone (LHRH) agonists on xenografts of the DU 145 human androgen-independent prostate cancer cell line in nude mice. Int. J. Cancer. 1998;76:506–511
  81. Vaux DL, Korsmeyer SJ. Cell death in development. Cell. 1999;96:245–254
  82. Riedl SJ, Shi Y. Molecular mechanisms of caspase regulation during apoptosis. Nat. Rev. Mol. Cell. Biol. 2004;5:897–907
  83. Thorburn A. Death receptor-induced cell killing. Cell Signal. 2004;16:139–144
  84. Jiang X, Wang X. Cytochrome C-mediated apoptosis. Annu. Rev. Biochem. 2004;73:87–106
  85. Maundrell K, Antonsson B, Magnenat E, Camps M, Muda M, Chabert C, et al. Bcl-2 undergoes phosphorylation by c-Jun N-terminal kinase/stress-activated protein kinases in the presence of the constitutively active GTP-binding protein Rac1. J. Biol. Chem. 1997;272:25238–25242
  86. Yamamoto K, Ichijo H, Korsmeyer SJ. BCL-2 is phosphorylated and inactivated by an ASK1/Jun N-terminal protein kinase pathway normally activated at G(2)/M. Mol. Cell. Biol. 1999;19:8469–8478
  87. Deng Y, Ren X, Yang L, Lin Y, Wu X. A JNK-dependent pathway is required for TNFalpha-induced apoptosis. Cell. 2003;115:61–70
  88. Lin A. Activation of the JNK signaling pathway: breaking the brake on apoptosis. Bioessays. 2003;25:17–24
  89. Hamilton JA, Stewart LM, Ajayi L, Gray IC, Gray NE, Roberts KG, et al. The expression profile for the tumour suppressor gene PTEN and associated polymorphic markers. Br. J. Cancer. 2000;82:1671–1676
  90. Vlietstra RJ, van Alewijk DC, Hermans KG, van Steenbrugge GJ, Trapman J. Frequent inactivation of PTEN in prostate cancer cell lines and xenografts. Cancer Res. 1998;58:2720–2723
  91. Paweletz CP, Charboneau L, Bichsel VE, Simone NL, Chen T, Gillespie JW, et al. Reverse phase protein microarrays which capture disease progression show activation of pro-survival pathways at the cancer invasion front. Oncogene. 2001;20:1981–1989
  92. Malik SN, Brattain M, Ghosh PM, Troyer DA, Prihoda T, Bedolla R, et al. Immunohistochemical demonstration of phospho-Akt in high Gleason grade prostate cancer. Clin. Cancer Res. 2002;8:1168–1171
  93. Kreisberg JI, Malik SN, Prihoda TJ, Bedolla RG, Troyer DA, Kreisberg S, et al. Phosphorylation of Akt (Ser473) is an excellent predictor of poor clinical outcome in prostate cancer. Cancer Res. 2004;64:5232–5236
  94. Lin J, Adam RM, Santiestevan E, Freeman MR. The phosphatidylinositol 3′-kinase pathway is a dominant growth factor-activated cell survival pathway in LNCaP human prostate carcinoma cells. Cancer Res. 1999;59:2891–2897
  95. Graff JR, Konicek BW, McNulty AM, Wang Z, Houck K, Allen S, et al. Increased AKT activity contributes to prostate cancer progression by dramatically accelerating prostate tumor growth and diminishing p27Kip1 expression. J. Biol. Chem. 2000;275:24500–24505
  96. Hill MM, Hemmings BA. Inhibition of protein kinase B/Akt. implications for cancer therapy. Pharmacol. Ther. 2002;93:243–251
  97. Carson JP, Kulik G, Weber MJ. Antiapoptotic signaling in LNCaP prostate cancer cells: a survival signaling pathway independent of phosphatidylinositol 3′-kinase and Akt/protein kinase B. Cancer Res. 1999;59:1449–1453
  98. Tanaka Y, Gavrielides MV, Mitsuuchi Y, Fujii T, Kazanietz MG. Protein kinase C promotes apoptosis in LNCaP prostate cancer cells through activation of p38 MAPK and inhibition of the Akt survival pathway. J. Biol. Chem. 2003;278:33753–33762
  99. Bodmer JL, Holler N, Reynard S, Vinciguerra P, Schneider P, Juo P, et al. TRAIL receptor-2 signals apoptosis through FADD and caspase-8. Nat. Cell Biol. 2000;2:241–243
  100. Chen X, Thakkar H, Tyan F, Gim S, Robinson H, Lee C, et al. Constitutively active Akt is an important regulator of TRAIL sensitivity in prostate cancer. Oncogene. 2001;20:6073–6083
  101. Emons G, Grundker C, Gunthert AR, Westphalen S, Kavanagh J, Verschraegen C. GnRH antagonists in the treatment of gynecological and breast cancers. Endocr. Relat. Cancer. 2003;10:291–299
  102. Kimura A, Ohmichi M, Kurachi H, Ikegami H, Hayakawa J, Tasaka K, et al. Role of mitogen-activated protein kinase/extracellular signal-regulated kinase cascade in gonadotropin-releasing hormone-induced growth inhibition of a human ovarian cancer cell line. Cancer Res. 1999;59:5133–5142
  103. Kim JH, Park DC, Kim JW, Choi YK, Lew YO, Kim DH, et al. Antitumor effect of GnRH agonist in epithelial ovarian cancer. Gynecol. Oncol. 1999;74:170–180
  104. Gunthert AR, Grundker C, Hollmann K, Emons G. Luteinizing hormone-releasing hormone induces JunD-DNA binding and extends cell cycle in human ovarian cancer cells. Biochem. Biophys. Res. Commun. 2002;294:11–15
  105. Pfarr CM, Mechta F, Spyrou G, Lallemand D, Carillo S, Yaniv M. Mouse JunD negatively regulates fibroblast growth and antagonizes transformation by ras. Cell. 1994;76:747–760
  106. Imai A, Takagi A, Horibe S, Takagi H, Tamaya T. Fas and Fas ligand system may mediate antiproliferative activity of gonadotropin-releasing hormone receptor in endometrial cancer cells. Int. J. Oncol. 1998;13:97–100
  107. Gunthert AR, Grundker C, Bottcher B, Emons G. Luteinizing hormone-releasing hormone (LHRH) inhibits apoptosis induced by cytotoxic agent and UV-light but not apoptosis mediated through CD95 in human ovarian and endometrial cancer cells. Anticancer Res. 2004;24:1727–1732
  108. Gunthert AR, Grundker C, Bongertz T, Schlott T, Nagy A, Schally AV, et al. Internalization of cytotoxic analog AN-152 of luteinizing hormone-releasing hormone induces apoptosis in human endometrial and ovarian cancer cell lines independent of multidrug resistance-1 (MDR-1) system. Am. J. Obstet. Gynecol. 2004;191:1164–1172
  109. Grundker C, Gunthert AR, Millar RP, Emons G. Expression of gonadotropin-releasing hormone II (GnRH-II) receptor in human endometrial and ovarian cancer cells and effects of GnRH-II on tumor cell proliferation. J. Clin. Endocrinol. Metab. 2002;87:1427–1430
  110. Choi KC, Auersperg N, Leung PC. Expression and antiproliferative effect of a second form of gonadotropin-releasing hormone in normal and neoplastic ovarian surface epithelial cells. J. Clin. Endocrinol. Metab. 2001;86:5075–5078
  111. Kim KY, Choi KC, Park SH, Chou CS, Auersperg N, Leung PC. Type II gonadotropin-releasing hormone stimulates p38 mitogen-activated protein kinase and apoptosis in ovarian cancer cells. J. Clin. Endocrinol. Metab. 2004;89:3020–3026
  112. Friedman AJ, Daly M, Juneau-Norcross M, Rein MS, Fine C, Gleason R, et al. A prospective, randomized trial of gonadotropin-releasing hormone agonist plus estrogen-progestin or progestin ‘add-back’ regimens for women with leiomyomata uteri. J. Clin. Endocrinol. Metab. 1993;76:1439–1445
  113. Wang Y, Matsuo H, Kurachi O, Maruo T. Down-regulation of proliferation and up-regulation of apoptosis by gonadotropin-releasing hormone agonist in cultured uterine leiomyoma cells. Eur. J. Endocrinol. 2002;146:447–456
  114. Mizutani T, Sugihara A, Nakamuro K, Terada N. Suppression of cell proliferation and induction of apoptosis in uterine leiomyoma by gonadotropin-releasing hormone agonist (leuprolide acetate). J. Clin. Endocrinol. Metab. 1998;83:1253–1255
  115. Huang SC, Tang MJ, Hsu KF, Cheng YM, Chou CY. Fas and its ligand, caspases, and bcl-2 expression in gonadotropin-releasing hormone agonist-treated uterine leiomyoma. J. Clin. Endocrinol. Metab. 2002;87:4580–4586
  116. Bifulco G, Miele C, Pellicano M, Trencia A, Ferraioli M, Paturzo F, et al. Molecular mechanisms involved in GnRH analogue-related apoptosis for uterine leiomyomas. Mol. Hum. Reprod. 2004;10:43–48
  117. Yang E, Zha J, Jockel J, Boise LH, Thompson CB, Korsmeyer SJ. Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. Cell. 1995;80:285–291
  118. Sharoni Y, Bosin E, Miinster A, Levy J, Schally AV. Inhibition of growth of human mammary tumor cells by potent antagonists of luteinizing hormone-releasing hormone. Proc. Natl Acad. Sci. USA. 1989;86:1648–1651
  119. Vincze B, Palyi I, Daubner D, Kremmer T, Szamel I, Bodrogi I, et al. Influence of luteinizing hormone-releasing hormone agonists on human mammary carcinoma cell lines and their xenografts. J. Steroid Biochem. Mol. Biol. 1991;38:119–126
  120. Yano T, Korkut E, Pinski J, Szepeshazi K, Milovanovic S, Groot K, et al. Inhibition of growth of MCF-7 MIII human breast carcinoma in nude mice by treatment with agonists or antagonists of LH-RH. Breast. Cancer Res. Treat. 1992;21:35–45
  121. Yano T, Pinski J, Szepeshazi K, Halmos G, Radulovic S, Groot K, et al. Inhibitory effect of bombesin/gastrin-releasing peptide antagonist RC-3095 and luteinizing hormone-releasing hormone antagonist SB-75 on the growth of MCF-7 MIII human breast cancer xenografts in athymic nude mice. Cancer. 1994;73:1229–1238
  122. Keri G, Balogh A, Szoke B, Teplan I, Csuka O. Gonadotropin-releasing hormone analogues inhibit cell proliferation and activate signal transduction pathways in MDA-MB-231 human breast cancer cell line. Tumour Biol. 1991;12:61–67
  123. Grundker C, Gunthert AR, Hellriegel M, Emons G. Gonadotropin-releasing hormone (GnRH) agonist triptorelin inhibits estradiol-induced serum response element (SRE) activation and c-fos expression in human endometrial, ovarian and breast cancer cells. Eur. J. Endocrinol. 2004;151:619–628
  124. Szepeshazi K, Schally AV, Juhasz A, Nagy A, Janaky T. Effect of luteinizing hormone-releasing hormone analogs containing cytotoxic radicals on growth of estrogen-independent MXT mouse mammary carcinoma in vivo. Anticancer Drugs. 1992;3:109–116
  125. Chen A, Kaganovsky E, Rahimipour S, Ben-Aroya N, Okon E, Koch Y. Two forms of GnRH are expressed in human breast tissue and overexpressed in breast cancer: a putative mechanism for the antiproliferative effect of GnRH by down-regulation of acidic ribosomal phosphoproteins P1 and P2. Cancer Res. 2002;62:1036–1044
  126. Emons G, Kavanagh JJ. Hormonal interactions in ovarian cancer. Hematol. Oncol. Clin. North Am. 1999;141:1–14
  127. Schally AV, Nagy A. Chemotherapy targeted to cancers through tumoral hormone receptors. Trends Endocrinol. Metab. 2004;15:300–310
  128. Schally AV, Nagy A. Cancer chemotherapy based on targeting of cytotoxic peptide conjugates to their receptors on tumors. Eur. J. Endocrinol. 1999;141:1–14
  129. Arencibia JM, Schally AV, Halmos G, Nagy A, Kiaris H. In vitro targeting of a cytotoxic analog of luteinizing hormone-releasing hormone AN-207 to ES-2 human ovarian cancer cells as demonstrated by microsatellite analyses. Anticancer Drugs. 2001;12:71–78
  130. Chatzistamou L, Schally AV, Nagy A, Armatis P, Szepeshazi K, Halmos G. Effective treatment of metastatic MDA-MB-435 human estrogen-independent breast carcinomas with a targeted cytotoxic analogue of luteinizing hormone-releasing hormone AN-207. Clin. Cancer Res. 2000;6:4158–4165
  131. Palyi I, Vincze B, Lovas S, Mezo I, Pato J, Kalnay A, et al. Gonadotropin-releasing hormone analogue conjugates with strong selective antitumor activity. Proc. Natl Acad. Sci. USA. 1999;96:2361–2366
  132. Qi L, Nett TM, Allen MC, Sha X, Harrison GS, Frederick BA, et al. Binding and cytotoxicity of conjugated and recombinant fusion proteins targeted to the gonadotropin-releasing hormone receptor. Cancer Res. 2004;64:2090–2095
  133. Wurmbach E, Yuen T, Ebersole BJ, Sealfon SC. Gonadotropin-releasing hormone receptor-coupled gene network organization. J. Biol. Chem. 2001;276:47195–47201
  134. Kakar SS, Winters SJ, Zacharias W, Miller DM, Flynn S. Identification of distinct gene expression profiles associated with treatment of LbetaT2 cells with gonadotropin-releasing hormone agonist using microarray analysis. Gene. 2003;308:67–77

PII: S0304-3835(05)00202-8

doi: 10.1016/j.canlet.2005.02.038

Cancer Letters
Volume 234, Issue 2 , Pages 109-123 , 28 March 2006